The actions of Protease Activated Receptor-2 (PAR2) are thought to be involved in pain, musculoskeletal inflammation, neuroinflammatory disorders, airway inflammation, itch, dermatitis, colitis and related conditions. The protease activated receptors are composed of four family members (PAR1, PAR2, PAR3 and PAR4), which are G-protein coupled receptors activated by a proteolytic cleavage of the N-terminal region of the receptor (Ramachandran, Hollenberg et al, Nature Reviews Drug Discovery, 2012, 11 69-86). Upon proteolytic cleavage, the receptor then is activated for second messenger activation and cellular responses. Many enzymes are known to cleave the N-terminal region of PAR receptors to initiate this process such as thrombin, trypsin, mast cell tryptase, kallikreins and related enzymes in the inflammatory and coagulation cascades. Other ligands are known to activate the receptor, such as short peptides like SLIGKV-NH2 (SEQ ID NO.: 2), SLIGLR-NH2 (SEQ ID NO.: 3) or small molecule ligands such as GB-110 (Fairlie et al, Journal of Medicinal Chemistry, 2013, 56, 7477-7497).
PAR2 expression has been shown to be increased in synovial lining, chondrocytes, and tissues in human rheumatoid arthritis and animal models of arthritis (Amiable, N. et al, Bone, 44, 1143-1150). PAR2 also potentiates signaling via channels such as TRPV1 (Dai, et al Journal of Innate Immunology, 2010, 2, 495-504), a ligand-gated ion channel involved in inflammatory pain. PAR2 signaling is also known to sensitize TRPV1 in vivo, resulting in thermal hyperalgesia.
The inhibition of PAR2 receptors is known to be responsible for inflammatory signaling pathways. In mice lacking the PAR2 receptor, there is a delayed onset of inflammation (Linder et al, Journal of Immunology 2000, 165, 6504-6510). Other rodent PAR2 knockout studies have demonstrated that PAR2 plays an important role in pathophysiology of many disease conditions such as pain, musculoskeletal inflammation such as osteoarthritis, neuroinflammatory disorders, airway inflammation, itch, dermatitis, colitis and related conditions (Fairlie et al, Journal of Medicinal Chemistry, 2013, 56, 7477-749). PAR2 receptor antagonists such as GB88 have also been shown to block inflammatory responses in vivo such as collagen-induced arthritis model in rats (Fairlie et al, FASEB Journal, 2012, 26, 2877-2887).
PAR2 antagonists are thus thought likely to provide benefit to numerous people and to have a potential to alleviate pain and inflammation related conditions.